The fluoroquinolones, 1-cyclopropyl-6-fluoro-8-methoxy-7-(4-amino-3,3-dimethylpiperidin-1-yl)-1,4-dihydro-4-oxo-quinoline3-carboxylic acid hydrochloride and 1-cyclopropyl-6-fluoro-8-methoxy-7-(4amino-3,3-dimethylpiperidin-1-yl)-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid methane sulfonate (“methane sulfonate” being also termed as “mesylate”) having the formulae I and II
are described in our pending U.S. Patent Application publication Nos. 2003/0096812 and 20030216568 and WO Application publication Nos. 02/085886 and 03/050107. Racemic and optically active enantiomeric forms of 1-cyclopropyl-6-fluoro-8methoxy-7-(4-amino-3,3-dimethylpiperidin-1-yl)-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid are described in these US patent applications and WO applications.
The processes for preparing the respective hydrochloride and methane sulfonate salts of the racemic mixture and optical enantiomers of 1-cyclopropyl-6-fluoro-8-methoxy-7-(4-amino-3,3-dimethylpiperidin-1-yl)-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid are described in our pending US patent application publication No. 2003/0096812 (the '812 application). The respective polymorphs A-1 and A-2 of the hydrochloride salt forms of the racemic mixture and enantiomeric isomers of 1-cyclopropyl-6-fluoro-8-methoxy-7-(4-amino-3,3-dimethylpiperidin-1-yl)-1,4-dihydro-4-oxo-quinoline-3carboxylic acid hydrochloride are also described in US application publication No. 2003/0216568 and corresponding WO application publication 03/050107.
Additionally, polymorphic forms A-3 and A-4 of levorotatory isomer S-(−)-1-cyclopropyl-6-fluoro-8-methoxy-7-(4-amino-3,3-dimethylpiperidin-1-yl)-1,4-dihydro4-oxo-quinoline-3-carboxylic acid hydrochloride are described in our co-pending Indian patent application No. 1199/MUM/2003 and U.S. application No. 60/523,872, from which this application claims priority, both of which are completely incorporated herein by reference.
According to our pending US patent application publication No. 2003/0216568 (the '568 application), the levorotatory enantiomer S-(−)-1-cyclopropyl-6-fluoro-8-methoxy-7-(4-amino-3,3-dimethylpiperidin-1-yl)-1,4-dihydro-4-oxo-quinoline3-carboxylic acid hydrochloride is produced by the method of the '812 application. On dissolution in methanol and cooling, a polymorph designated A-1 having a crystalline form is obtained, and the polymorph is characterized by Powder X-ray diffraction spectroscopy, infrared spectroscopy and differential scanning calorimetry. The '568 application also describes a second polymorph designated A-2 having a crystalline form prepared by dissolving the levorotatory S-(−)-1-cyclopropyl-6-fluoro-8-methoxy-7-(4-amino-3,3-dimethylpiperidin-1-yl)-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid hydrochloride in 50% aqueous isopropanol and subsequent cooling. The A-2 crystalline polymorph being characterized by Powder X-ray diffraction spectroscopy, infrared spectroscopy and differential scanning calorimetry.
Although our co-pending US patent application publication Nos. '812 and '568 describe mesylate salts of the racemic mixture and optical enantiomers of 1-cyclopropyl-6-fluoro-8-methoxy-7-(4-amino-3,3-dimethylpiperidin-1-yl)-1,4-dihydro4-oxo-quinoline-3-carboxylic acid, the applications do not describe that the mesylate salts can exist in more than one polymorphic form.
We have now found novel pharmaceutically suitable hydrochloride salt polymorphic forms (designated A-3) and methane sulfonate salt polymorphic forms (designated B-1 and B-2) of the racemic mixture (±)-1-cyclopropyl-6-fluoro-8-methoxy-7-(4-amino-3,3-dimethylpiperidin-1-yl)-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid, dextrorotatory isomer R-(+)-1-cyclopropyl-6-fluoro-8-methoxy-7-(4-amino-3,3-dimethylpiperidin-1-yl)-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid, and S-(−)-1-cyclopropyl-6-fluoro-8-methoxy-7-(4-amino-3,3-dimethylpiperidin-1-yl)-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid and additionally polymorph A-4 of hydrochloride salt of the S-(−)-1-cyclopropyl-6-fluoro-8-methoxy-7-(4-amino-3,3-dimethylpiperidin-1-yl)-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid, and novel processes to prepare and isolate them.
These polymorphic forms A-3, A-4, B-1 and B-2 also have antibacterial activity. The compounds disclosed in our co-pending US patent application publications Nos. 2003/0096812 and 2003/0216568 also have antibacterial activity.